Carotid artery stenosis is a well-known cause of atheroembolic stroke. Stroke prevention in these patients has been the focus of intense investigation. Cognitive impairment is a more insidious but poorly understood outcome in patients with asymptomatic carotid stenosis who have not suffered a stroke. Cognitive function describes how a person produces and controls mental processes such as thinking, learning, and problem solving. It is an important outcome measure that affects patient well-being and their ability to live independent productive lies. It is well-known that cognitive impairment coexists in patients with stroke from carotid stenosis. However, isolated cognitive deficits in patients with asymptomatic carotid stenosis have not been looked for, and have therefore not been reported in any detail. Asymptomatic carotid stenosis affects 2-12% of people. With 23.4 million veterans in the country, at least 1 million (4.3%) have asymptomatic carotid stenosis and are at risk for cognitive impairment. A subset analysis of the Cardiovascular Health Study found cognitive decline in 34% of 32 patients with asymptomatic carotid stenosis. In this proposal, we will define the extent of initial and progressive cognitive impairment in veterans with carotid stenosis who are currently labeled as asymptomatic in the absence of a focal neurologic deficit (stroke, transient ischemic attack). Programs to prevent, postpone, or mitigate cognitive impairment in patients with carotid stenosis will depend on the identification of mediators for cognitive impairment. Microembolic brain injury and cerebral hypoperfusion have been associated with cognitive impairment in elderly individuals. Therefore plaque architecture, plaque composition, microembolic counts, serum inflammatory markers, and cerebral hypoperfusion are likely mediators of impaired cognition in patients with asymptomatic carotid stenosis. As part of this proposal, we will identify the biological mechanisms by which carotid stenosis could result in cognitive impairment. The goal of this proposal is to perform a systematic, adequately powered study to measure the magnitude of cognitive impairment in asymptomatic carotid stenosis, its impact on quality of life, and its potential pathophysiological mechanisms. Information from this study will define an unsuspected morbidity of carotid stenosis and identify subsets of patients at risk for cognitive impairment. It will form the foundation for future studies on prevention, pre-emptive treatment, or rehabilitation of patients with carotid stenosis. It will also improve the selection of patients with carotid stenosis to decrease unnecessary revascularization procedures. Specific Aim 1 will assess if patients with asymptomatic carotid stenosis differ in cognitive function compared to age-matched controls without carotid stenosis but with similar vascular risk profiles. We hypothesize that in patients with asymptomatic carotid stenosis 50% who survive stroke free for 2 years; the change in overall and domain-specific cognitive function will be significantly different compared to those without stenosis. The study will recruit 284 subjects and will detect a clinically significant difference in cognitive score with 90% power. We will use a novel battery of cognitive tests specifically developed to address the unique issues relating to carotid stenosis. Specific Aim 2 will define plaque-morphometric, biologic, and hemodynamic characteristics that correlate with cognitive impairment in patients with asymptomatic carotid stenosis. We hypothesize that carotid plaque architecture, plaque composition, microembolic counts, serum pro-inflammatory markers, and cerebral hypoperfusion could each mediate cognitive decline over a 2-year follow-up period. We will implement a novel clinical 3D B-mode ultrasound imaging technique developed to obtain reliable serial plaque measurements. Specific Aim 3 will measure the impact of cognitive impairment on quality of life. We hypothesize that at 2 years, regardless of plaque features, cognitive impairment will correlate with a reduction in health-related quality of life measures. PUBLIC HEALTH RELEVANCE: Carotid artery plaques are known to cause stroke. Cognitive impairment is an insidious but poorly under- stood problem in patients with carotid plaques. Cognitive function describes how we perform mental processes such as thinking, learning and problem solving. Asymptomatic carotid plaques may affect 1 million veterans who may be at risk for cognitive impairment. In this study, we will uncover the extent of cognitive impairment in veterans with carotid stenosis who are currently labeled asymptomatic. Programs to prevent or mitigate cog- nitive impairment will depend on identifying the mechanisms by which this occurs. We will use sophisticated 3D imaging techniques developed by our group to measure the structure and composition of plaques, number of particles breaking off from them, blood levels of chemicals that could disrupt them, and blood flow restriction to the brain from them. This will help identify patients at risk for cognitive impairment who may benefit from pre- ventative measures and improve selection of patients to decrease unnecessary surgical procedures.